In­dia to bounce back as clin­i­cal re­search hub

BioSpectrum (India) - - FRONT PAGE - Narayan Kulka­rni (With in­puts from Aish­warya Venkatesh and Dr Man­beena Chawla)

In­dia was con­sid­ered as an all-time favoured des­ti­na­tion for clin­i­cal tri­als. Most of the out­sourced stud­ies are phase III stud­ies where In­dia has a di­verse pool of pa­tients. Af­ter 2010 there was ma­jor set­back in the CRO in­dus­try in In­dia. Drug Con­troller Gen­eral of In­dia (DCGI) ap­provals were de­layed and multi­na­tional spon­sors stepped back out­sourc­ing stud­ies to In­dia. But slowly post 2016 DCGI has been gen­er­ous enough in prov­ing ap­provals and on­line ap­pli­ca­tion sys­tem has brought a lot of dif­fer­ence. In­dian Clin­i­cal Trial mar­ket and clin­i­cal trial ser­vices is ex­pected to grow sig­nif­i­cantly along with trends.

With 17% of the global pop­u­la­tion and 20% of the world’s dis­ease bur­den, In­dia faces a ‘triple bur­den’ caused by com­mu­ni­ca­ble dis­ease, non-com­mu­ni­ca­ble dis­ease and so­cio-be­hav­ioral ill­ness. The in­creas­ing dis­ease bur­den is pro­pel­ling the phar­ma­ceu­ti­cal and biotech­nol­ogy in­dus­try to bring up new chem­i­cal en­ti­ties into the mar­ket at a higher rate. Most com­pa­nies are out­sourc­ing the clin­i­cal tri­als of their newly devel­oped drugs to var­i­ous con­tract re­search or­ga­ni­za­tions as this could save them the has­sles of reg­u­la­tory is­sues and pa­tient re­cruit­ment bur­den from the re­search and de­vel­op­ment phase.

Mak­ing his point on triple bur­den of dis­eases, Naz Haji, SVP & Managing Direc­tor, Quin­tilesIMS In­dia said “We have dis­eases that are close to be­ing erad­i­cated in other re­gions like cholera and tu­ber­cu­lo­sis, and at the same time must con­tend with ris­ing rates of di­a­betes, car­dio-vas­cu­lar and other life­style-re­lated dis­eases. De­spite this high bur­den of dis­ease, ac­cord­ing to www.clin­i­cal­tri­als.gov, less than 1.4% of global clin­i­cal tri­als are car­ried out in In­dia and we need to be do­ing more for our pa­tients. Be­sides our large pop­u­la­tion of treat­ment-naïve pa­tients, In­dia also has ex­cel­lent site in­fra­struc­ture, skilled in­ves­ti­ga­tors and cost ef­fi­cien­cies.”

Mar­ket Trends

Ac­cord­ing to Bos­ton Con­sult­ing Group, 48% ($30 bil­lion) of all clin­i­cal re­search in­vest­ment in 2017 will be spent on out­sourced ser­vices. In­dia is home to 16 per cent of the world’s pop­u­la­tion, 20 per cent of the global dis­ease bur­den, yet it has less than 2 per cent of clin­i­cal tri­als reg­is­tered world­wide.

On the cur­rent trends in CRO space, Divya Chan­drad­hara, Direc­tor of Bio Ag­ile Ther­a­peu­tics said “To­tal num­ber of reg­is­tered stud­ies world­wide is about 253,462 (as on September 1, 2017) as per clin­i­cal­trails.gov. 5673 trails have been reg­is­tered on Clin­i­cal Tri­als Registry- In­dia (CTRI) till date. In 2010 when In­dia

“In­dia presents one of the most promis­ing tri­als are­nas avail­able to­day. Cur­rently, In­dia rep­re­sents 17% (1/6th) of the world’s pop­u­la­tion, with ge­net­i­cally di­verse pa­tient base in var­i­ous dis­ease ar­eas (1/5th or 20% of the global dis­ease bur­den) and only 1-2 % of all global clin­i­cal tri­als. High preva­lence of both the de­vel­op­ing and devel­oped world pro­vides ac­cess to a va­ri­ety of dis­eases in­clud­ing ac­cess to a large pool of eth­ni­cally di­verse and of­ten treat­ment-naïve pa­tients. With a high stan­dard of med­i­cal care avail­able via ex­pert clin­i­cians (in­clud­ing those re­turn­ing west­ern-trained physi­cians), ac­cess to tech­nol­ogy and com­pet­i­tive op­er­a­tional costs, In­dia of­fers an at­trac­tive op­tion, for those want­ing qual­ity data col­lected from an in­ter­na­tion­ally har­mo­nized en­vi­ron­ment.” - Dr Aparna Parikh, Ex­ec­u­tive Direc­tor – Sci­en­tific Af­fairs, Pe­di­atrics & In­fec­tious Dis­eases, PRA Health Sci­ences

“We have been work­ing with the DCGI of­fice for the last two years and look­ing at where the ob­sta­cles are, and try­ing to de­sign the en­tire path­way of clin­i­cal de­vel­op­ment. This is be­cause we had a num­ber of dif­fer­ent stake­hold­ers telling us about the is­sues they were fac­ing, not only from the com­mer­cial side but also from the aca­demic and sci­en­tific side, and also the in­dus­try. We have now re­vised the ICMR eth­i­cal guide­lines, which was last touched upon in 2006. So we have in­cluded a lot of new chap­ters in that, on pub­lic health re­search, use of gene ther­apy and so on. The draft guide­lines will be of­fi­cially re­leased very soon. The in­dus­try will be of course ben­e­fited by them. ” - Dr Soumya Swami­nathan, Direc­tor Gen­eral, ICMR

was in peak of the get­ting ma­jor MNC stud­ies there was al­most 500 tri­als reg­is­tered in CTRI, in 2013 it was only 107 stud­ies, in 2014 we have 133 tri­als reg­is­tered, in 2015 its about 121 stud­ies, in 2016, 84 stud­ies, in 2017 about 45 stud­ies till date and its slowly pick­ing.”

The per­cent­age of clin­i­cal tri­als reg­is­tered in di­a­betes, CAD, asthma, COPD, epilepsy, schizophre­nia, malaria, and tu­ber­cu­lo­sis are more in In­dia com­pared to other na­tions. Still In­dia is lag­ging far be­hind the west­ern coun­tries as well as other Asian coun­tries like China and Ja­pan in the to­tal num­ber of tri­als reg­is­tered.

There are about 400 + com­pa­nies (multi­na­tional and lo­cal) in In­dia which have been of­fer­ing clin­i­cal re­search ser­vices. About the num­ber of em­ploy­ees Divya Chan­drad­hara ob­served that ma­jor CROs in­clude more than 20,000 em­ploy­ees world­wide, but many CROs are small, with fewer than 50 em­ploy­ees. Staff in­cludes en­try-level Co-or­di­na­tors, As­so­ci­ates, Pro­ject man­agers, Med­i­cal writ­ers, Data man­agers, Statis­ti­cians.

Though there was a slight slow­down dur­ing last five years, the clin­i­cal tri­als in­dus­try in In­dia is see­ing an up­ward trend. Shar­ing her thoughts Dr Chaitra Har­sha, Managing Direc­tor, Vipra­gen Bio­sciences said “There are sev­eral rea­sons be­hind the pos­i­tive growth in clin­i­cal phase I and phase II tri­als in In­dia, the least be­ing the proac­tive ap­proach and busi­ness-friendly ‘Make in In­dia’ ini­tia­tive of the In­dian govern­ment.”

Needs at­ten­tion

The re­cent amend­ments in the reg­u­la­tory frame­work have sig­nif­i­cantly stream­lined the clin­i­cal trial review process. Cen­tral Drugs Stan­dard Con­trol Or­ga­ni­za­tion

“Though In­dia makes up 16% of the world's pop­u­la­tion and 20% of the world's dis­ease bur­den, less than 1.4% of global clin­i­cal tri­als are car­ried out in the coun­try. Of 236,329 on­go­ing global clin­i­cal stud­ies, only 3,016 stud­ies are be­ing done in In­dia, plac­ing it way be­hind the USA, Europe, Ja­pan, China, Malaysia and Tai­wan. The low num­ber ranks In­dia in the fifth po­si­tion in Asia.” - Dr Chaitra Har­sha, Managing Direc­tor, Vipra­gen Bio­sciences

(CDSCO), the na­tional reg­u­la­tory body for In­dian phar­ma­ceu­ti­cals and med­i­cal de­vices, and serves, has ini­ti­ated on­line sub­mis­sion of ap­pli­ca­tions and mon­i­tor­ing of clin­i­cal tri­als in the coun­try in order to im­prove trans­parency, ac­count­abil­ity and ef­fi­ciency in pro­cess­ing of tri­als. The ap­pli­ca­tion and review process needs to be made sim­pler with fewer ad­min­is­tra­tive hur­dles and less un­cer­tain­ties as­so­ci­ated with the ap­proval time­lines. Faster ap­proval time­lines would make it con­ducive for more clin­i­cal stud­ies to be con­ducted in In­dia.

Though DCGI has made the ap­pli­ca­tion process sim­pler com­pared to pre­vi­ous and re­duced the timeline for get­ting ap­proval the num­ber of stud­ies con­ducted is still not sig­nif­i­cant. There are many other is­sues that need im­me­di­ate at­ten­tion of the reg­u­la­tory agen­cies.

Re­fer­ring to the is­sues Dr Chaitra Har­sha said “There is a lack of aware­ness among the re­searchers re­gard­ing the reg­is­tra­tion of clin­i­cal tri­als in clin­i­cal trial reg­istries. An­other rea­son could be the avail­abil­ity of a lim­ited num­ber of rec­og­nized courses for train­ing physi­cians and other health­care pro­fes­sion­als in­volved in the con­duc­tance of clin­i­cal tri­als, re­sult­ing in short­age of trained man­power.”

Hence to meet the grow­ing de­mands of clin­i­cal re­search and to in­crease the num­ber of reg­is­tered tri­als in the coun­try, she sug­gested that In­dia needs to train more qual­i­fied, eth­i­cal clin­i­cal in­ves­ti­ga­tors, skilled nurses and bio­statis­ti­cians to suit the clin­i­cal trial ap­praisal. With ex­pe­ri­enced clin­i­cal re­searchers and tech­no­log­i­cal de­vel­op­ments, In­dia is sure to con­trib­ute as a ma­jor clin­i­cal trial des­ti­na­tion for the global clin­i­cal re­search in the near fu­ture.

On chal­lenges be­fore the CROs, Dr Aparna Parikh, Ex­ec­u­tive Direc­tor – Sci­en­tific Af­fairs, Pe­di­atrics & In­fec­tious Dis­eases, PRA Health Sci­ences said “Ethics Com­mit­tees (ECs) have been em­pow­ered to reg­u­late clin­i­cal re­search at each in­di­vid­ual study site and are re­spon­si­ble for safe­guard­ing the rights and safety of re­search par­tic­i­pants. It is there­fore im­por­tant to en­sure that these ECs have trained man­power, ad­e­quate stan­dard op­er­at­ing pro­ce­dures, suf­fi­cient ad­min­is­tra­tive sup­port and com­pli­ance with Sched­ule Y re­quire­ments. Also, the high re­cruit­ment in In­dia can chal­lenge both the sites and the study mon­i­tors as strug­gle to keep up. Hence the need to se­lect sites with trained in­ves­ti­ga­tors, site staff and ac­cred­ited ethics com­mit­tees. As clin­i­cians and sites in the ma­jor met­ros get busier with more and more clin­i­cal tri­als, it is im­por­tant to de­velop newer sites by ed­u­cat­ing and train­ing in­ves­ti­ga­tors, clin­i­cal re­search pro­fes­sion­als and ethics com­mit­tee mem­bers.”

Out­comes of global in­spec­tions in re­cent past (data in­tegrity and GCP vi­o­la­tions), lack of con­ducive reg­u­la­tory frame­work, knee-jerk im­ple­men­ta­tion of reg­u­la­tions, de­lays in clin­i­cal trial per­mis­sions, cross­par­tic­i­pa­tion risk (BA/BE stud­ies), need of stream­lin­ing clin­i­cal re­search pro­cesses and close col­lab­o­ra­tion of all stake­hold­ers in the ecosys­tem are the other is­sues that need se­ri­ous at­ten­tion said Dr Shrini­vas Savale, Phar­ma­ceu­ti­cal and Bio­phar­ma­ceu­ti­cal Con­sul­tant, Ahmed­abad.

“I think the big­gest chal­lenge we have in In­dia is the need to re­store con­fi­dence and trust amongst

“Pre­vi­ously due to reg­u­la­tory ap­proval de­lays some spon­sor com­pa­nies were di­vert­ing to con­duct their tri­als in coun­tries like China, Tai­wan and Malaysia go­ing by their ex­per­tise and speedy clear­ances. One ex­cit­ing de­vel­op­ment is that ap­provals for clin­i­cal tri­als are now tak­ing about six to seven months, which is the global stan­dard. It used to be 15 months in In­dia a cou­ple of years back.” - Divya Chan­drad­hara, Direc­tor, Bio Ag­ile Ther­a­peu­tics

global stake­hold­ers in do­ing re­search in In­dia. We have come out of a very chal­leng­ing reg­u­la­tory en­vi­ron­ment and now have regulation that is sci­en­tific, bal­anced and pa­tient-cen­tric. Our reg­u­la­tors are com­mit­ted to bring­ing tri­als back to In­dia and it is a re­spon­si­bil­ity that all stake­hold­ers have to play a role in so that our pa­tients have ac­cess to the best and new­est treat­ment and ther­a­pies. It is also im­por­tant that we cre­ate more aware­ness about the high qual­ity of clin­i­cal re­search

“In­dian com­pa­nies need to fo­cus on qual­ity. Greater em­pha­sis and con­sis­tent out­look on all as­pects of qual­ity is es­sen­tial to gain recog­ni­tion in the global plat­form. From the reg­u­la­tory per­spec­tive, even though much has been done in the last cou­ple of years there is space to im­prove on the level of clar­ity that is needed on cer­tain is­sues and also on the trained man­power needed to im­ple­ment the plans.” - Dr Saral Thangam, CEO & Managing Direc­tor, Nor­wich Clin­i­cal Ser­vices

done in In­dia. It is un­for­tu­nate that the one or two in­stances of trans­gres­sion that we read about in the me­dia seem to drive the nar­ra­tive around clin­i­cal re­search in our coun­try. There is so much of high qual­ity clin­i­cal re­search be­ing done in In­dia and we must en­sure the world knows about it,” Naz Haji of Quin­tilesIMS In­dia added.

Dr Aparna Parikh fur­ther ob­served that me­dia can play a ma­jor role to sup­port clin­i­cal re­search in In­dia by ed­u­cat­ing the pub­lic on re­search and de­vel­op­ment and dis­sem­i­nat­ing ac­cu­rate in­for­ma­tion about clin­i­cal tri­als. Both me­dia and pa­tient sup­port groups can help pro­mote pub­lic aware­ness and en­gage­ment to in­crease the trust, sup­port, par­tic­i­pa­tion in clin­i­cal re­search and thus pa­tients gain ac­cess to safe and ef­fec­tive new treat­ments for un­met med­i­cal needs. Ad­verse me­dia re­ports, long, un­cer­tain reg­u­la­tory ap­proval time­lines will only de­lay in­tro­duc­tion of new and rel­e­vant ther­a­pies, wors­en­ing the prob­lem of drug lag in our coun­try.

Global com­pa­nies lack trust in In­dian CRO’s due to data qual­ity is­sues cre­ated by few CRO’s. Ethics com­mit­tee ap­proval for stud­ies is one of the chal­lenge. Divya Chan­drad­hara, said that main­te­nance of high qual­ity data, im­prove­ments in in­fra­struc­ture, ac­com­moda­tive reg­u­la­tory en­vi­ron­ment, will play ma­jor role in im­prov­ing the In­dian mar­ket size in clin­i­cal re­search.

There is def­i­nitely a need to safe­guard the in­ter­ests of re­search par­tic­i­pants. Dr Shrini­vas Savale ob­served that the sec­tor be­ing highly reg­u­lated strict com­pli­ance to the good clin­i­cal prac­tice (GCP), good lab­o­ra­tory prac­tice (GLP) and other good prac­tices need to be mon­i­tored and ver­i­fied by qual­i­fied peo­ple/reg­u­la­tory in­spec­tors. Me­dia also needs to be sen­si­tive to this in­dus­try em­pha­siz­ing on the larger ben­e­fits of clin­i­cal re­search. Most im­por­tantly all the con­tribut­ing play­ers for core and sup­port­ing roles need to com­mit for main­tain­ing the high stan­dards of con­duct clin­i­cal re­search, with

“Given the sup­port­ive reg­u­la­tory en­vi­ron­ment we now have in In­dia and the com­mit­ment from reg­u­la­tors to en­cour­ag­ing more clin­i­cal re­search in the coun­try, the out­look for clin­i­cal re­search is pos­i­tive. We are likely to also see a lot more lo­cal in­no­va­tion and R&D for ill­nesses preva­lent in our coun­try which bodes well for our pa­tients. We are also likely to see, as in the rest of the world, greater adop­tion and in­te­gra­tion of tech­nol­ogy and data and an­a­lyt­ics in the con­duct of clin­i­cal re­search.”

- Naz Haji, SVP & Managing Direc­tor, Quin­tilesIMS In­dia

ethics and qual­ity at its cen­tre, year-on-year.

In spite of the many chal­lenges, op­por­tu­ni­ties and strengths In­dia has, will help it to bounce back from a trou­bled pe­riod that the in­dus­try has ex­pe­ri­enced in 2013-14 for con­duct­ing clin­i­cal tri­als. Dr Saral Thangam, CEO & Managing Direc­tor, Nor­wich Clin­i­cal Ser­vices said “There have been con­sid­er­able im­prove­ments from the per­spec­tive of time­lines, and pre­dictabil­ity of out­comes for clin­i­cal trial ap­pli­ca­tions. There are mul­ti­ple pos­i­tive ini­tia­tives by the govern­ment bod­ies to en­gage the stake­hold­ers. Sev­eral of the rules that were im­ped­ing trial con­duct in In­dia have been repealed or mod­i­fied to al­low a rea­son­able clin­i­cal trial frame­work to emerge.”

S P c Q d RT QPR

With re­cent set­backs in the in­ter­na­tional reg­u­la­tory scru­tiny has cost dearly to the spon­sors glob­ally and

the ‘non­com­pli­ant and in­tegrity lapses’ have cre­ated a huge neg­a­tiv­ity about In­dian clin­i­cal re­search sec­tor. “There is a need for con­cen­trated ef­forts from all the stake­hold­ers, espe­cially CROs who have been per­form­ing the world-class re­search for last cou­ple of decades and reg­u­la­tory agency en­sur­ing trans­par­ent and ro­bust sys­tem as well as con­ducive reg­u­la­tory at­mos­phere safe­guard­ing in­ter­ests of all con­trib­u­tors, to im­prove the im­age of In­dian Clin­i­cal Re­search in­dus­try. These ef­forts have started re­flect­ing with pos­i­tive out­comes of reg­u­la­tory in­spec­tions at the CROs and sites as well as changes in the reg­u­la­tory sys­tems. Def­i­nitely the in­dus­try will bounce back in next 5-7 years,” Dr Shrini­vas Savale said.

The in­dus­try play­ers are op­ti­mistic about the growth of the in­dus­try in the com­ing years. Given the mere pop­u­la­tion of the coun­try and the dis­ease bur­den, In­dia qual­i­fies to be ma­jor clin­i­cal re­search hub in the years to come. The other ma­jor rea­sons for the same are sim­pli­fi­ca­tion of reg­u­la­tory pro­ce­dures; latest proac­tive steps taken by the govern­ment; en­cour­age­ment to lo­cal stake­hold­ers in clin­i­cal re­search and global in­cen­tives to grow, sums up Dr Chaitra Har­sha.

Mak­ing her point Divya Chan­drad­hara said “In­dia has the po­ten­tial to es­tab­lish it­self as a hub for global clin­i­cal tri­als. Emerg­ing tech­nolo­gies, qual­ity out­put and

“Re­cent ac­tions from reg­u­la­tory au­thor­i­ties – au­to­ma­tion/ on­line sub­mis­sion of ap­pli­ca­tions, smoothen­ing the process of im­port/ex­port of bi­o­log­i­cal sam­ples, reg­is­tra­tion of ethics com­mit­tees, sci­en­tific ap­proach to grant­ing the per­mis­sion for first-in-man stud­ies on case-by-case ba­sis, im­proved reg­u­la­tory vig­i­lance of reg­u­la­tory agency and re­cruit­ment of com­pe­tent reg­u­la­tory staff/train­ing of the staff to up­date the skills and un­der­stand­ing in the clin­i­cal re­search – in­di­ca­tions of im­prov­ing the clin­i­cal re­search ecosys­tem and boost­ing the sec­tor.” - Dr Shrini­vas Savale, Phar­ma­ceu­ti­cal and Bio­phar­ma­ceu­ti­cal Con­sul­tant, Ahmed­abad

faster trial ap­provals will help us to achieve the goal.”

“It must be recog­nised that all stake hold­ers have a role to play in this. In­dian pharma com­pa­nies, CROs, Ethics com­mit­tees, reg­u­la­tors, the pub­lic and the me­dia have to act in a re­spon­si­ble and sus­tain­able man­ner to sup­port clin­i­cal re­search in In­dia. The an­nounce­ment of ICMR re­gard­ing the shar­ing of data is def­i­nitely a

pos­i­tive step for­ward,” Dr Saral Thangam added.

With reg­u­la­tory re­forms in place, In­dia is cer­tainly once again on an up­ward cy­cle as its ap­peal to both in­ter­na­tional and lo­cal spon­sor com­pa­nies rec­og­nize the ad­van­tages and op­por­tu­ni­ties avail­able. The un­der­stand­ing of tri­als con­tin­ues to grow in this rel­a­tively young trial arena pro­vid­ing strong data qual­ity to match its re­cruit­ment abil­i­ties.

“In­dia will con­tinue to in­crease in ap­peal as it in­creases its cul­ture of qual­ity along­side its pro­tec­tion of pa­tient safety ma­tu­rity in the tri­als arena. Im­proved reg­u­la­tions, train­ing and ed­u­ca­tion of re­search pro­fes­sion­als, in­creased base of qual­i­fied and trained in­ves­ti­ga­tors and sup­port­ing staff, high qual­ity data will once again make In­dia an at­trac­tive des­ti­na­tion for global clin­i­cal tri­als,” con­cludes Dr Aparna Parikh, of PRA Health Sci­ences.

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